This invention relates to substituted aminoethylphosphonate compositions and therapeutic uses thereof. More specifically, the present invention relates to novel xcex1-substituted-xcex2-aminoethylphosphonate and xcex1-substituted-xcex2-aminovinylphosphonate derivatives, processes for their preparations, pharmaceutical compositions containing them and their use in therapy, for lowering plasma levels of apo (a) and apo (a) associated lipoprotein (lipoprotein(a) or xe2x80x9cLp(a)xe2x80x9d), for lowering plasma levels of apo B and apo B associated lipoproteins (low density lipoproteins and very low density lipoproteins), and for lowering plasma levels of total cholesterol.
Lp(a) is a LDL-like lipoprotein wherein the major lipoprotein, apo B-100, is covalently linked to an unusual glycoprotein, apoprotein(a). The covalent association between apo(a) and apo B to form Lp(a) is a secondary event which is independent of the plasma concentration of apo B. Due to its structural similarity to plasminogen, apo(a) interferes with the normal physiological thrombosis-hemostasis process by preventing thrombolysis, that is clot dissolution (see e.g., Biemond B J, Circulation 1997, 96(5) 1612-1615). The structural feature of Lp(a), where the LDL lipoprotein is linked to apo(a), is thought to be responsible for its atherogenic and thrombogenic activities.
Elevated levels of Lp(a) have been associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, cerebral infarction, restenosis following balloon angioplasty and stroke. A recent epidemiologic study has provided the clinical proof of a positive correlation between plasma Lp(a) concentrations and the incidence of heart disease (A. G. Bostom, et al., Journal of American Medical Association 1996, 276, p. 544-548).
Patients that have Lp(a) levels in excess of 20-30 mg/dl run a significantly increased risk of heart attacks and stroke. An effective therapy for lowering Lp(a) does not exist at present because cholesterol lowering agents such as the HMGCoA reductase inhibitors do not lower Lp(a) plasma concentrations. The only compound that lowers Lp(a) is niacin, but the high doses necessary for activity are accompanied with unacceptable side-effects. There is, therefore, an unmet therapeutic need for agents that effectively reduce elevated levels of Lp(a).
International applications WO 97/20307, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar, SmithKline Beecham) describe a series of xcex1-amino phosphonates which have Lp(a) lowering activity. There however remains the need to identify further compounds having Lp(a) lowering activity.
The present invention provides, in a first aspect, a compound of formula (Ia): 
or a compound of formula (Ib): 
in which:
X1, X2, X3, X4 and X5 are independently hydrogen, hydroxy, hydroxymethyl, C1-C3 alkoxymethyl, straight or branched C1-C8 alkyl, straight or branched C1-C8 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, norbornyl, adamantyl, amino, primary or secondary amino substituted with C1-C3 alkyl, cyano, halogen (F, Cl, Br, I), and nitro; or
X2 may be combined with X3, or X4 may be combined with X5, to form a 5- to 6-membered alkylidenedioxy ring optionally substituted with a C1-C4 alkyl group; or
X4 may be combined with X5 to form a 5- to 6-membered alkylidene ring optionally substituted with a C1-C4 alkyl group;
R1 and R2 which may be the same or different, are independently hydrogen or a straight or branched C1-C6 alkyl;
B is CH2 or CH2xe2x80x94CH2;
n is zero or 1;
Z0 is H, straight or branched C1-C4 alkyl, C1-C4 alkylcarbonyl, or C1-C4 perfluoroalkylcarbonyl;
m is zero or an integer from 1 to 4;
Het is an optionally substituted heteroaryl group comprising at least one nitrogen atom, or a pharmaceutically acceptable salt thereof;
for a compound of formula (Ia), Y1, Y2 and Y3 are independently hydrogen or C1-C4 alkyl and for a compound of formula (Ib), Y3 is hydrogen or C1-C4 alkyl.
The compound of formula (Ib) may be the Z-isomer, the E-isomer, or a mixture thereof.
Compounds of the present invention include:
(Z)-diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
(Z)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
(Z)-diisopropyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-Diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-diisopropyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-ethylphosphonate;
diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-pyridyl)-amino]-ethylphosphonate;
diisopropyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-pyridyl) amino]-ethylphosphonate;
(Z)-diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
(Z)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
(E)-diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
(E)-diisopropyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-vinylphosphonate;
diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
diisopropyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(2-methyl)pyridyl))-amino]-vinylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(2-methyl)pyridyl))-amino]-ethylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(2-methoxy)pyridyl))-amino]-vinylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(2-methoxy)pyridyl))-amino]-ethylphosphonate;
(Z)-diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(pyrazinyl)-amino]-vinylphosphonate;
(Z)-diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(pyrazinyl)-amino]-vinylphosphonate;
(Z)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(pyrazinyl)-amino]-vinylphosphonate;
(E)-diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(pyrazinyl)-amino]-vinylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(pyrazinyl)-amino]-vinylphosphonate;
diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(pyrazinyl)-amino]-ethylphosphonate;
diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(pyrazinyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(pyrazinyl)-amino]-ethylphosphonate;
(Z)-diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
(Z)-diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
(E)-diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
(E)-diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
diisopropyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(2-pyrimidinyl)-amino]-ethylphosphonate;
(Z)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
(Z)-diisopropyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-vinylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-pyrimidinyl)-amino]-vinylphosphonate;
(E)-diethyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-diisopropyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
(E)-diethyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-vinylphosphonate;
(E)-diethyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(5-(2-methylpyridyl))-amino]-vinylphosphonate;
(E)-diisopropyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(5-(2-methylpyridyl))-amino]-vinylphosphonate;
diethyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-ethylphosphonate;
diisopropyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-pyridyl)-amino]-ethylphosphonate;
diethyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diisopropyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(5-(2-methylpyridyl))-amino]-ethylphosphonate;
diisopropyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(5-(2-methylpyridyl))-amino]-ethylphosphonate;
(E)-diisopropyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-vinylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-pyrimidinyl)-amino]-ethylphosphonate;
(E)-diethyl xcex1-(3-ethoxy-4-hydroxy-5-methylphenyl)-xcex2-[N-(3-pyridyl)-amino]-vinylphosphonate;
diethyl xcex1-(3-ethoxy-4-hydroxy-5-methylphenyl)-xcex2-[N-(3-pyridyl)-amino]-ethylphosphonate;
(E)-diethyl xcex1-(3-ethoxy-4-hydroxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-vinylphosphonate;
diethyl xcex1-(3-ethoxy-4-hydroxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
(E)-diisopropyl xcex1-(3-ethoxy-4-hydroxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-vinylphosphonate;
diisopropyl xcex1-(3-ethoxy-4-hydroxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(4,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(4,6-dimethylpyrimidinyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(4-methoxy-6-methylpyrimidinyl))-amino]-ethylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-pyrimidinyl)-amino]-vinylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-pyrimidinyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(2-methylpyrimidinyl)-amino]-ethylphosphonate;
(Z)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(4-methylpyrimidinyl))-amino]-vinylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(4-methylpyrimidinyl))-amino]-vinylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(4-methylpyrimidinyl))-amino]-ethylphosphonate;
(Z)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(2,6-dimethylpyrimidinyl))-amino]-vinylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(2,6-dimethylpyrimidinyl))-amino]-vinylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(2,6-dimethylpyrimidinyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-thiazolyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(5-methylthiazolyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(1,3,4-thiadiazolyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(5-methyl-1,3,4-thiadiazolyl))-amino]-ethylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(5-methylpyrazinyl))-amino]-vinylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(5-methylpyrazinyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(6-methylpyridazinyl))-amino]-ethylphosphonate;
(E)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(4-(1,3,5-trimethylpyrazolyl))-amino]-vinylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(4-(1,3,5-trimethylpyrazolyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-benzothiazolyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxyphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(3-hydroxy-4-methoxyphenyl)-xcex2-[N-(3-(2,6-dimethyl)pyridyl))-amino]-ethylphosphonate;
dimethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-pyridyl)-amino]-ethylphosphonate;
dimethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(1,3-dimethylpyrazolyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-isoxazolyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(5-methylisoxazolyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(5-(3-methylisoxazolyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(4-methyloxazolyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(2-(4-methylthiazolyl))-amino]-ethylphosphonate;
diethyl (xcex1-phenyl-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-chlorophenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-methoxyphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-methyl-N-(3-picolyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-methyl-N-(2-pyridyl)-amino]-ethylphosphonate;
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-methyl-N-(2-(2-ethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-methyl-xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate;
diethyl xcex1-(3,5-dimethyl-4-hydroxyphenyl)-xcex2-[N-(pyrazinyl)-amino]-ethylphosphonate;
diethyl xcex1-(3-tert-butyl-4-hydroxy-5-methylphenyl)-xcex2-[N-(pyrazinyl)-amino]-ethylphosphonate;
diethyl xcex1-methyl-xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-pyrazinyl)-amino]-ethylphosphonate; and
diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethyl)-aminopyridyl]-propylphosphonate.
Compounds of the present invention also include the following racemates and enantiomers:
(xc2x1)-diethyl xcex1-(3,5-dimethoxy-4-hydroxyphenyl)-xcex2-[N-(pyrazinyl)-amino]-ethylphosphonate;
(xc2x1)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(pyrazinyl)-amino]-ethylphosphonate;
(xc2x1)-diisopropyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-3-(2,6-dimethyl)pyridyl-amino]-ethylphosphonate;
(xc2x1)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate; and
(+) and (xe2x88x92)-diethyl xcex1-(4-hydroxy-3-methoxy-5-methylphenyl)-xcex2-[N-(3-(2,6-dimethylpyridyl))-amino]-ethylphosphonate, in particular the (+)-enantiomer, and pharmaceutically acceptable salts thereof, especially the dihydrogen phosphate salt.
One aspect of the present invention provides for a pharmaceutical composition comprising a compound of formula (Ia) or formula (Ib) and a pharmaceutically acceptable excipient. Hereinafter compounds of formula (Ia) and compounds of formula (Ib) are collectively termed xe2x80x9ccompounds of formula (I).xe2x80x9d
The present invention also provides for therapeutic uses of the compounds of formula (I). In one aspect, the invention provides for a method of decreasing plasma levels of apo (a) and lipoprotein(a), in reducing plasma levels of apo B and LDL cholesterol and in decreasing plasma total cholesterol. The present invention also provides further methods including: a method of treatment of thrombosis by increasing thrombolysis through decreasing plasma levels of apo (a) and lipoprotein(a); a method of treatment of restenosis following angioplasty by decreasing plasma levels of apo (a) and lipoprotein(a); a method of prevention and/or treatment of atherosclerosis by decreasing plasma levels of apo (a) and lipoprotein(a) or by decreasing plasma levels of apoprotein B and LDL cholesterol; a method of prevention and/or treatment of hypercholesterolemia; a method of prevention and/or treament of atherosclerosis by lowering cholesterol in patients that are resistant to treatment with statins; and a method of prevention and/or treatment of atherosclerosis in association with a compound such as a statin which decreases cholesterol synthesis.
The present invention relates to the compounds of formula (I) and their uses for lowering plasma levels of apo (a), Lp(a), apo B, apo B associated lipoproteins (low density lipoproteins and very low density lipoproteins) and for lowering plasma levels of total cholesterol.
In relation to compounds of formula (I), in preferred embodiments, X1 is hydrogen, or methyl, X2 is methoxy, ethoxy, methyl or hydroxy, X3 is hydrogen, hydroxy, methoxy, methyl, ethyl or hydroxymethyl, X4 is hydrogen, methoxy or methyl and X5 is hydrogen. In a preferred combination, X2 is methoxy, X3 is hydroxy and X4 is methyl or methoxy, preferably methyl. Preferably, n is zero, so that (B), is replaced with a direct bond. Preferably R1 and R2 are C1-C3 alkyl, more preferably C2 or C3, and in particular wherein R1 and R2 are independently ethyl or isopropyl. Preferably m is zero. Preferably, Y1, Y2 and Y3 are independently selected from hydrogen or C1-C4 alkyl, more preferably Y2 and Y3 are each hydrogen for a compound of formula (Ia) and Y3 is hydrogen for a compound of formula (Ib).
When used herein the term xe2x80x9cheteroarylxe2x80x9d refers to, unless otherwise defined, a single or a fused ring containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to four substituents. Each ring suitably has from 4 to 7, preferably 5 or 6 ring atoms. A fused ring system may include carbocyclic rings and need include only one heteroaryl ring.
Representative examples of Het include pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, thiadiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazinyl, and imidazolyl which may be unsubstituted or substituted by up to four substituents (for pyridyl and benzothiazolyl), three substituents (pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl), two substituents (thiazolyl, isoxazolyl, triazinyl and imidazolyl) or one substituent (thiadiazolyl) which may be the same or different and selected from straight or branched C1-C4 alkyl or alkoxy, hydroxy, hydroxymethyl, halogen (F, Cl, Br, I), or an amino group optionally substituted with C1-C4 alkyl. Preferably, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, thiadiazolyl, benzothiazolyl, pyrazolyl, or triazinyl is unsubstituted or substituted by methyl, methoxy, dimethoxy or dimethyl. Preferred examples of Het are 2,6-dimethylpyridyl and pyrazinyl.
Pharmaceutically acceptable salts for use in the present invention include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed from inorganic and organic acids. Representative examples thereof include maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
It will be appreciated that certain compounds of the present invention, in particular those of formula (Ia), will comprise one or more chiral centres so that compounds may exist as stereoisomers, including diastereoisomers and enantiomers. The present invention covers all such stereoisomers, and mixtures thereof, including racemates. The compounds of formula (Ib) of the present invention comprise the individual E- and Z-diastereoisomers and mixtures thereof.
Since the compounds of the present invention, in particular compounds of formula (Ia) and (Ib) (collectively the compounds of formula (I)), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.
When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of formula (I).
The present invention also relates to the unexpected discovery that compounds of formula (I) are effective for decreasing apo(a) production in vitro and Lp(a) production in vivo in Cynomolgus monkeys. This species has been selected as the animal model as its Lp(a) is similar in immunologic properties to human Lp(a) and occurs in almost identical frequency distribution of plasma concentrations, see e.g., N. Azrolan et al; J. Biol. Chem., 266, 13866-13872 (1991). In the in vitro assay, compounds of formula (I) have been shown to reduce the secretion of apo (a) which is secreted in free form from the primary cultures of the Cynomolgus monkey hepatocytes. These results are confirmed by the in vivo studies performed on the same animal species showing the potent decrease of Lp(a) by compounds of formula (I). Therefore the compounds of this invention are useful for decreasing apo (a) and Lp(a) in man and thus provide a therapeutic benefit.
Accordingly in a further aspect, this invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy, in particular as a Lp(a) lowering agent. Elevated plasma and tissue levels of Lp(a) are associated with accelerated atherosclerosis, abnormal proliferation of smooth muscle cells and increased thrombogenesis and expressed in disease states such as, for instance: coronary heart disease, peripheral artery disease, intermittent claudication, thrombosis, restenosis after angioplasty, extra-cranial carotid atherosclerosis, stroke and atherosclerosis occurring after heart transplantion.
Furthermore, the compounds of the present invention have been found to have potent cholesterol lowering properties. Thus, studies performed in Cynomolgus monkeys have shown that the compounds of the present invention decrease total plasma cholesterol, in particular LDL cholesterol. It is now well established that a high level of LDL cholesterol is a major risk factor for atherosclerotic diseases. In addition, the compounds of the present invention were also shown to decrease the levels of apoprotein B (apo B) which is the main protein of LDL and the main ligand for LDL receptors. The mechanism of this decrease in apo B and in apo B-associated LDL does not involve inhibition of cholesterol synthesis, which is the mechanism demonstrated for the statins. Therefore, compounds of the present invention are useful for lowering cholesterol in patients who are resistant to treatment with a statin, and, conversely, also have a synergistic effect for lowering cholesterol in those patients who are responding to treatment with statins.
Thus, compounds of the present invention are of use in therapy as cholesterol lowering agents. Furthermore, because of their dual profile in lowering plasma Lp(a) and plasma cholesterol, compounds of formula (I) are of use in therapy for the prevention and/or treatment of both the acute and chronic aspects of atherosclerosis.
Compounds of the present invention may also be of use in preventing and/or treating the above mentioned disease states in combination with anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal, anti-inflammatory or anti-hypertension agents. Examples of the above include cholesterol synthesis inhibitors such as statins, for instance atorvastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (also referred to as S-4522, Astra Zeneca), anti-oxidants such as probucol, insulin sensitisers such as a PPAR gamma activator, for instance G1262570 (Glaxo Wellcome) and the glitazone class of compounds such as rosiglitazone (Avandia, SmithKline Beecham), troglitazone and pioglitazone, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs.
For therapeutic use the compounds of the present invention will generally be administered in a standard pharmaceutical composition. Accordingly in a further aspect, the invention provides for a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. Suitable excipients and carriers are well known in the art and will be selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compositions may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules, ovules or lozenges either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for xe2x80x9cexample, enough salts or glucose to make the solution isotonic with blood. The choice of form for administration as well as effective dosages will vary depending, inter alia, on the condition being treated. The choice of mode of administration and dosage is within the skill of the art.
The compounds of formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions or as solids for example, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavoring or coloring agents. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of structure (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats. Preferably the composition is in unit dose form such as a tablet or capsule.
Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of formula (1) or a pharmaceutically acceptable salt thereof calculated as the free base.
The compounds of the invention will normally be administered to a subject in a daily dosage regimen. For an adult patient this may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
The present invention also relates to a process for preparing novel xcex1-substituted-xcex2-aminoethylphosphonate derivatives of formula (I), which is described below.
Compounds of formula (Ib) may be prepared by a process which comprises treating a phosphonate of formula (II): 
in which Y1, X1, X2, X3, X4, X5, B, n, R1 and R2 are as previously defined and Y4 is hydrogen or C1-C4 alkyl; with an amine of formula (III):
H2Nxe2x80x94(CH2)mxe2x80x94Hetxe2x80x83xe2x80x83(III) 
in which m and Het are as previously defined,
The coupling reaction between (II) and (III) can be carried out in several ways. In the first variant the phosphonate (II) is condensed with the amine (III) under imine forming conditions. Suitably, the condensation may be effected with or without a catalyst in a solvent such as ether, tetrahydrofuran, benzene, toluene, ethanol or glacial acetic acid. Suitable catalysts include molecular sieve, magnesium sulfate, trialkyl orthoformate, an acid such as glacial acetic acid, p-toluenesulfonic acid, thionyl chloride, titanium tetrachloride, boron trifluoride etherate, or a base such as potassium carbonate. The reaction is suitably carried out in the range of 0xc2x0 C. to the boiling point of the solvent being used. A particularly advantageous procedure consists in heating to reflux a toluene mixture of equimolar amounts of phosphonate (II) and amine (III) with concomitant elimination of water in a Dean-Stark apparatus. Another variant consists in heating a mixture of equimolar amounts of (II) and (III) in glacial acetic acid at a temperature between room temperature and boiling point, preferably at 40xc2x0 C. In the third variant, the reaction between the phosphonate (II) and the amine (III) is carried out in presence of hydrogen and a catalyst in a hydrogenation apparatus. Suitable catalysts include Raney Nickel and suitable solvents include acetic acid and the suitable hydrogenation conditions include atmospheric pressure at room temperature.
Both of the first two mentioned variants of the condensation of a phosphonate of formula (II) with an amine of formula (III) afford compounds of formula (Ib). The two isomers can be separated by column chromatography and recrystallization. The structures of these isomers are ascertained by spectroscopic means, MS and in particular NMR, thanks to the characteristic absorption of the olefinic proton. In the (Z)-isomer, the olefinic proton displays a large coupling constant, J=ca 40-43 Hz, due to the trans Hxe2x80x94Cxe2x95x90Cxe2x80x94P coupling. In the (E)-isomer, this value is much smaller, J=15 Hz, due to the cis Hxe2x80x94Cxe2x95x90Cxe2x80x94P coupling.
Compounds of formula (Ia) in which one of Y2 and Y3 is hydrogen can be prepared by reducing the double bond of compounds of formula (Ib). A convenient reduction method is the catalytic hydrogenation using palladium or platinum adsorbed on charcoal as catalysts in a solvent such as ethanol or acetic acid at a pressure between 1 and 4 atm and a temperature between room temperature and 40xc2x0 C. The reduction can also be carried out by means of a complex hydride reagent such as sodium borohydride or sodium cyanoborohydride in a polar solvent such as methanol, ethanol, isopropanol or n-propanol at a temperature between room and reflux temperature. A further convenient reduction method is the use of a zinc modified sodium cyanoborohydride reagent generated from a mixture of NaBH3CN: ZnCl2 in a 2:1 molar ratio in a solvent selected from diethyl ether, tetrahydrofuran, dimethoxyethane and methanol at a temperature between room temperature and reflux temperature; the reaction can be accelerated by the addition of a higher boiling solvent selected from ethanol, isopropanol, n-propanol, isobutanol or n-butanol and heating to reflux the resulting mixture.
The phosphonate of formula (II) may be prepared by reacting the corresponding phosphonate of formula (IV): 
in which Y1, X1, X2, X3, X4, X5, B, n, R1 and R2 are as previously defined, with ethyl formate (if Y4 is hydrogen) or with a carboxylic acid derivative Y4xe2x80x94COxe2x80x94T where Y4 is C1-C4 alkyl as previously defined and T is O-(C1-C4 alkyl), halogen (F, Cl, Br, I) or xe2x80x94OOY4 (wherein Y4 is C1-C4 alkyl), under alkaline conditions. Suitable conditions comprise reacting the phosphonate (IV) with a strong base, for instance n-butyllithium or lithium diisopropylamide in a solvent such as tetrahydrofuran at a temperature between xe2x88x9278xc2x0 C. to 0xc2x0 C.
A compound of formula (IV) in which Y1 is C1-C4 alkyl may be readily prepared from a corresponding compound of formula (IV) in which Y1 is hydrogen by the alkylation thereof, for instance using a combination of n-butyl lithium and a C1-C4 alkyl iodide, protecting if necessary any hydroxyl groups on the phenyl ring.
When any of the substituents X1, X2, X3, X4, X5 is a hydroxy group, giving a reactive phenol hydroxy group, it may be useful to protect such a hydroxy group, to avoid troublesome side reactions which may otherwise occur under the strongly alkaline reaction conditions employed. A particularly effective way of protecting the OH group is to convert it into an alkyl silyl ether, such as trimethyl silyl ether (Me3Si ether or Tms ether) or a t-butyldimethyl silyl ether (tBuMe2Si ether or Tbs ether). An integral part of this invention is the conversion of a phosphonate of formula (IV) comprising a hydroxy group into the corresponding Tbs ether. Suitable protection reaction conditions are the use of t-butyldimethylsilyl chloride in presence of imidazole in dimethylformamide. Such a Tbs protected phosphonate (IV) then undergoes the addition of ethyl formate (if Y4 is hydrogen) or a carboxylic acid derivative (if Y4 is C1-C4 alkyl) under strongly alkaline conditions to form a Tbs protected phosphonate (V). The Tbs protecting group can then be cleaved by fluoride reagents well established in the art to yield the phosphonate (II) wherein any of the substituents X1, X2, X3, X4, X5 can be a hydroxy group. Suitable deprotection reaction conditions involve reacting the Tbs protected compound with tetrabutyl ammonium fluoride in glacial acetic acid.
Such protection is not however always necessary and the reactive phenol hydroxy group is addressed by using a further equivalent of base and a final acid work up, to convert the xe2x80x9cphenolatexe2x80x9d back to a xe2x80x9cphenolxe2x80x9d.
The phosphonate of formula (IV) is prepared from commercially available compounds by well established methods.
The invention is further described in the following examples which are intended to illustrate the invention without limiting its scope. The abbreviations used in this application are the following:
In the tables, xe2x80x9cnxe2x80x9d is normal, xe2x80x9cixe2x80x9d is iso, xe2x80x9csxe2x80x9d is secondary and xe2x80x9ctxe2x80x9d is tertiary. In the description of the NMR spectra, respectively xe2x80x9csxe2x80x9d is singlet, xe2x80x9cdxe2x80x9d doublet, xe2x80x9cddxe2x80x9d double doublet, xe2x80x9ctxe2x80x9d triplet, xe2x80x9cqxe2x80x9d quadruplet and xe2x80x9cmxe2x80x9d multiplet. TsOH is p-toluenesulfonic acid monohydrate. The temperatures were recorded in degrees Celsius and the melting points are not corrected.
The structures of compounds described in the Examples were established by their infrared (IR), mass (MS) and nuclear magnetic resonance (NMR) spectra. The purity of the compounds was checked by thin layer, gas liquid or high performance liquid chromatographies.